Sunday, September 30, 2007

Today's editorial in The Toronto Star speaks against the mixed member proportional (MMP) electoral system and in favor of the status quo [Electoral reform a backward step].

The editors note that John Tory, the Progressive Conservative leader, is cool on the idea of MPP. The editors say,

Although the new system promises to deliver a legislature that mirrors the voters' intent, Tory notes it would also create two classes of members of the Legislature. Some would have a direct mandate from the voters; others could simply be appointed by party bosses.

If that is a democratic gain, it is hard to see.

Under the current system, nominees are appointed by a tiny number of dedicated people in each riding. Sometimes there are nomination meetings attended by a sizable crowd but those meetings are prone to stacking and all kinds of other abuses. The point is not that this is evil, the point is that the current system isn't as pristine as the first-past-the-post advocates claim.

The selection of party lists can be done in many different ways. It could be by party bosses in some dark room or it could be a much more open process. We don't know how it will work out under the new mixed member proportional system. I tend to think that a more open process will prevail since all of Ontario will be watching to see who's at the top of the list. In the case of the Green Party, for example, it will be interesting to see who the four new members will be if they pull 3% of the votes. It will certainly influence whether I cast a vote in their direction.

The same thing applies to all other parties. I won't be inclined to vote for a list of stooges, and you can be sure the other parties will be certain to point out the defects in party lists.

I think this argument against MMP is almost completely bogus. It's scaremongering and nothing more. One of the advantages of the MMP system, in my opinion, is the opportunity to get people into the legislature who might otherwise have little chance of getting elected. People who aren't wealthy enough to personally finance a campaign or a contested nomination, for example, or people who aren't good door-to-door campaigners but who would be an asset to Parliament. (Scientists, who aren't good at spinningframing sticking to the party line?)

The other argument used by the editors is more of the same whining we've heard dozens of times before.

Jurisdictions that have adopted some form or other of proportional representation – think of Italy, Israel, Germany, Belgium – have become notorious for chaotic politics and legislative gridlock.

While the occasional minority or coalition government beats the odds and performs well, far more commonly they are bitterly divisive, short-lived and paralyzed by conflict. Routinely, whoever heads the leading party is forced to cater to the demands of small, sometimes radical special-interest parties that enjoy no wide support, just to stay in power. That in itself is a distortion of the voters' will.

Let's get one thing straight, an inconvenient truth that's often ignored by all those who oppose MMP; as noted in the editorial, the last time a government of Ontario was elected by a clear majority was 70 yeas ago. Ever since then it's been the will of the people to cast their votes for a number of different parties such that no one party gets 50% of the votes. In other words, the people don't want majority governments. Nevertheless, majority governments are what the first-past-the-post system delivered in almost all elections. The Toronto Star editors are arguing that the real will of the people should be ignored in the interests of "stability." It's an argument that's often used against democracy.

No one suggests that first-past-the post is perfect. But Ontario's current system is democratic and robust, delivering strong, stable government that works. Why strain to "fix" what isn't broken?

If you're going to use this argument then please grant us the courtesy of explaining why you think "stability" should trump the clear preferences of the electorate and tell us just how far you're prepared to go in that direction.

There's no point in creating worse case scenarios in order to frighten people. I could just as easily bring up cases under first-past-the-post where a majority government, elected by less than 50% of the votes, thwarted the expressed will of the majority. "Stability" isn't always desirable at the expense of true democracy.

Yes, there are examples in foreign countries of legislatures that are gridlocked because the people want it that way. This happens under all kinds of electoral systems but it is more likely under true proportional systems and less likely under the mixed proportional system that we are considering. Will it happen in Ontario? I don't know, and neither do the editors. Personally, I think it's very unlikely given our history. It seems to me that there's very little chance that the government of Ontario would end up becoming beholding to a small party of four or five members.

Incidentally, all four of the countries mentioned (Italy, Belgium, Germany, Israel) are modern progressive countries with histories of social reforms that Canadians have emulated, or envied. The idea that nothing gets done in the legislatures of these countries does not stand up to close scrutiny.

[Photo Credit:Top: Police demonstrating how to maintain stability during the Queen's Park anti-poverty protest on June 15, 2000. Bottom: An example of the results produced by a first-past-the-post electoral system. "Thousands of teachers rallying at Queen's Park in the fall of 1997 were dismayed by government's lack of respect for the teaching profession." (Catholic Teachers Association) In 1995 Mike Harris' conservative government got 45% of the popular vote and 64% of the seats. In the 1999 election Mike Harris got 45% of the vote and 57% of the seats.]

Randy Schekman is a Professor at the University of California, Berkeley. He is one of the world's leading experts on sorting and secretion. The recent postings on The Signal Hypothesis and Signal Recognition particle focus on part of the sorting and secretion pathway. Schekman delivers three lectures on another part of this process, namely the formation of secretion vesicle in the cell and how they travel to the cell surface where they deliver their contents. The lectures are part of the iBioSeminars sponsored by The American Society for Cell Biology [Protein Secretion and Vesicle Traffic].

I think these lectures are examples of high quality science education unencumbered by any overt attempt to persuade the audience to adopt a particular social or political point of view.

Saturday, September 29, 2007

Every weekend TV Ontario broadcasts talks given by prominent thinkers at lectures given in Toronto. The broadcasts are at 4pm Saturday, repeated at 4pm on Sunday. You can also watch them on the Big Ideas website. The host, Andrew Moodie (photo below), often has insightful comments so it's better to watch the actual TV broadcast than the website video presentations. While Moodie is good, he's not as good as the previous host, Irshad Manji, in my opinion.

Today's lecturers will be of interest to Sandwalk readers. University of Toronto students will be familiar with Sue Varmuza.

Mark AbrahamsMarc Abrahams, editor of The Annals of Improbable Research and one of the organizers of the annual Ig-Nobel Prize ceremonies at Harvard University, discusses the work of scientists and academics that, "first makes you laugh, and then makes you think". Highlights of the lecture include discussions of a study that proves that Kansas is flatter than a pancake and a paper investigating The Forces Required to Drag Sheep Over Various Surfaces.

Sue VarmuzaThe second lecture in this episode of Big Ideas is by University of Toronto Zoology researcher Susannah Varmuza who discusses the evolving field of Epigenetics and what research into such things as mouse coat colour is telling scientists about the age-old "nature versus nurture" debate.

Friday, September 28, 2007

I suppose it's to be expected. People who are opposed to the Mixed Member Proportional system are making up stories in order to make it seem as bad as possible.

There seems to be a lot of confusion about the party lists. Here's a brief summary from the Vote for MMP website.

Elections Ontario will publish the selection of candidates that each party has democratically elected before the election.

This information will be widely available in advance, as required by law:

you'll know who party members selected before you vote for that party

you'll know whether a party valued having a good balance of women and men

you'll know whether a party valued having candidates from across the province, from rural and urban regions

you'll know whether a party valued having candidates who reflected Ontario's diverse population

you'll be able to decide before you vote whether a party created its list in a fair and democratic way

The important point here is that you will know who's on the list before you vote. You don't have to vote for the party if you don't like the list. Some people seem to think that a defeated candidate can be moved to the list after the votes have been counted and get elected by the back door.

Most people are worried about the party lists. They seem to think that the people on the list will be worthless party hacks. I don't think this is a major concern for two reasons.

Local ridings are already nominating worthless party hacks so the situation could hardly get any worse.

You won't vote for a party if their list is full of people who shouldn't be in the legislature.

Theme:TranscriptionThere are five different kinds of RNA polymerase in eukaryotes. Each of them is responsible for transcription of a different class of gene [Eukaryotic RNA Polymerases]. RNA polymerase III transcribes a heterogeneous class of genes that give rise to small RNAs.

The class III genes can be subdivided into four types depending on the location of the promoter regions. Type 1 genes possess an internal control region (ICR) that functions as the promoter. What this means is that the site of binding of the pol III transcription complex is within the gene. 5S RNA genes are the only kind of type 1 gene.

A cartoon drawing of the pol III transcription complex on a 5S RNA gene is shown above (Moran, Scrimgeour et al. 1994). The transcription factor TFIIIA binds to the internal control region (ICR). Another transcription factor, TFIIIC, binds TFIIIA and it, in turn, interacts with TFIIIB and RNA polymerase III. Transcription is initiated at a site (+1) upstream from the internal control region. Note that when the 5S RNA is produced it will contain the binding sites for TFIIIA. The significance of this fact will become clear in a few minutes.

The type 2 genes have an intragenic promoter with two binding sites, A and B. TFIIIC binds directly to this promoter causing the assembly of a transcription complex upstream in the same manner as the type 1 genes. Most of the transfer RNA (tRNA) genes are type 2 genes.

Type 3 genes have an upstream promoter and no internal promoter. In this sense they resemble the typical class II genes (transcribed by RNA polymerase II), such as those that encode protein. The U6 snRNA gene, a component of the spliceosome [RNA Splicing: Introns and Exons] is the prototype gene of this category.

Finally, type 4 genes have both an internal region where the regular class III transcription factors bind and a promoter at the 5′ end of the gene where regulatory transcription factors bind to control transcription. The 7SL RNA gene is a type 4 gene.

The RN7SL promoter has been characterized by Englert et al. (2004). The main features are shown in the diagram above. The solid blue box represents the gene—the DNA sequence corresponding to the 7SL RNA. There's a start site for transcription (+1) that's determined by the positioning of RNA polymerase III upstream. The transcription complex is assembled when TFIIIC binds to an internal control region specified by box A and box B. These are short DNA sequences (10 bp) that resemble the binding sites in tRNA genes. The upstream promoter region consists of a TATA box where RNA polymerase III binds and a regulatory site where unknown transcription factors (TF) bind.

Transcription terminates at a short stretch of thymidylate residues (T) at the 3′ end of the gene.

All four regulatory sites have to be present for maximum rates of transcription but—and this is important—there will still be low levels of transcription if only the A box and the B box are present.

From time to time cellular RNAs are copied by an enzyme called reverse transcriptase to create a DNA:RNA double-stranded molecule. On occasion this hybrid molecule will become integrated into the genome through a nonhomologous recombination event. (Sometimes the RNA strand will be replaced by DNA synthesis to create double-stranded DNA corresponding to the 7SL sequence.) This creates something called a processed pseudogene. Most genomes have hundreds of these pseudogenes derived from hundreds of different genes. They have arisen from accidental events over the course of millions of year of evolution and since there's no pressure to eliminate them, they are retained in the genome as junk.

Theme:
Junk DNAIf the processed pseudogene is derived from a class III gene there's a good chance that it will retain prompter activity because a good part of the promoter sequence was present in the RNA molecule. This is the case with 7SL pseudogenes and tRNA pseudogenes. They are often transcribed at low levels. The production of additional RNAs from the processed pseudogenes increases the probability that more pseudogenes will be created. More significantly, if the processed 7SL or tRNA pseudogenes happen to integrate near certain mobilization sequences they will be converted to retrotransposons because they can direct transcription of themselves—a necessary step in transposition. When this happens the pseudogenes will spread rapidly throughout the genome. We call this selfish DNA.

More than 10% of your genome consists of degenerate 7SL genes. That's where some of the junk DNA in your genome comes from.

"My tattoo is from an Irving Geis illustration of DNA. I was attracted to his attention to the molecular detail while also drawing in a representational spiral that doesn't ignore the basic beauty of the double helix. This particular sequence (I've BLASTED) is too short to be specific to only one gene, but one human gene it's found it is the 5' UTR of one of our tight junctions."-Matthew MacDougall, 4th year medical student

The figure is, indeed, a drawing by Irving Geis. It's based on a structure of the dodecamer CGCGAATTCGCG solved by Drew et al. (1981). You can download the PDB file yourself at 1BNA and look at it in your favorite structure viewer. Mine is RasMol. The DNA is in the typical B-DNA form first predicted by Watson & Crick.

THEME

Deoxyribonucleic Acid (DNA)I've prepared two views of this structure (below) so you see how it compares to the Geis drawing. The drawing is in some textbooks, notably Voet & Voet Biochemistry 3rd ed. (p.1108). If you look closely, you will notice that Geis has taken a few "liberties" with his drawing. It's not quite the same as the actual molecular model but it's pretty close. I don't think our 4th year medical student has to worry about anyone noticing the difference, except for curmudgeonly biochemistry Professors!

Well, at the top of the list are our old friends the neoconservatives, the folks who provided the intellectual rationale for Bush's war in Iraq, many of whom are now itching for a war with Iran. Norman Podhoretz, the neocon paterfamilias, has written a trifle called World War IV: The Long Struggle Against Islamofascism and loves to posit Ahmadinejad and Osama bin Laden—a far more dangerous character—as the heirs to Hitler and Stalin. "They follow the path of fascism, Nazism and totalitarianism," he writes. This is incendiary foolishness. Terrorists have the ability to wreak terrible damage intermittently, but they don't represent an existential threat to the U.S. Ahmadinejad commands no legions—not even the Hizballah forces in Lebanon that attacked Israel in the summer of 2006—and if Podhoretz doesn't know that, he should. Taking Ahmadinejad literally, as the neoconservatives do, is being disingenuous with lethal intent. It gives license to a conga line of politicians—especially Republicans running for �President—to strut their stuff by jumping on Ahmadinejad and Columbia University and liberals in general. Mitt Romney runs an ad in which he brags that he denied the milquetoast reformer Khatami a police escort to Harvard University in 2006. Now there's a man! The New York Daily News, owned by neoconservative Mort Zuckerman, runs the headline the evil has landed. The cable news networks hyperventilate. Even the president of Columbia University, Lee Bollinger, feels the need to demolish Ahmadinejad — elegantly, I must say — before the speech. A giant toxic bubble overwhelms the public square.

And then, there he is — and laughter is freedom's only appropriate reaction. The bubble bursts. He denies not only the Holocaust but also homosexuality? Suddenly, it all becomes obvious: We are being played by extremists on both sides. To be sure, Iran does arm Hizballah, and it does have an active nuclear program that may or may not be proved to have hostile intent, and it is making trouble for the U.S. in Iraq, supplying weapons to our enemies. These are all problems to be addressed soberly and perhaps even, eventually, with multilateral force. But the neoconservative campaign to transform Ahmadinejad into Hitler or Stalin, to pretend that he has the ability to destroy the world, to make a hoo-ha over letting the little man speak, is a cynical attempt to plump for war. Ahmadinejad may be ridiculous, but Podhoretz—who recently spent 45 minutes with Bush arguing for more war—isn't very funny at all.

University of Minnesota sociologists have found that the U.S. high school dropout rate is considerably higher than most people think -- with one in four students not graduating -- and has not improved appreciably in recent decades. Their findings point to discrepancies in the two major data sources on which most governmental and non-governmental agencies base their findings.

The U.S. Census Bureau’s Current Population Survey (CPS) is widely used by governmental and non-governmental sources -- from the Annie E. Casey Foundation to the White House -- to report high school dropout rates. The CPS paints a rosy picture, showing dropout rates at about 10 percent in recent years and declining some 40 percent over the past generation. On the other hand, measures of high school completion based on the National Center for Education Statistics’ Common Core of Data survey (CCD) paint a darker picture, with high school completion rates holding steady at about 75 percent in recent decades.

Here's the important question that everyone seems to ignore: What is the optimal high school dropout rate? Surely it shouldn't be zero because that would be setting the bar too low. It probably shouldn't be 50% because that sets the bar too high. What should it be, assuming that lack of ability to complete high school was the only reason for dropping out?

If we're interested in keeping students in high school by addressing those other reasons for dropping out, then how will we know if we're succeeding unless we establish the minimum dropout rate? Is 25% good?

[Photo Credit: "Joining nationwide demonstrations, high-school students in Valparaíso [Chile] take to the streets on May 30 [2006] to protest proposed changes in Chile's public education system." Eliseo Fernandez—Reuters /Landov (Encyclopedia Britanica Online)]

The sequence of the Giardia lamblia genome has just been published in this month's issue of Science [Morrison et al., 2007].

Giardia lamblia is a single-celled eukaryote with two nuclei and prominent flagella (undulipodia, cilia) [Giardia lamblia, Wikipedia]. In most classification schemes it is placed in the Diplomonadida group, which may or may not be accorded the rank of phylum [Giardia lamblia NCBI Taxonomy]. Giardia is an intestinal parasite that colonizes the small intestine causing diarrhea and sometimes pain and nausea.

Many of the press releases focus on the medical relevance of the work on Giardia but the direct quotations from the scientists involved in the project reveal the real purpose behind this genome sequencing project. For example, Mitchell Sogin is quoted in the Marine Biogical Laboratory press release [Giardia Genome Unlocked].

“We embarked upon this genome project because of its importance to human health and suggestions from earlier molecular analyses that Giardia represents a very early-diverging lineage in the evolutionary history of eukaryotes,” Sogin says. “Giardia’s genome content and architecture support these theories about the parasite’s ancestral character.”

Sogin has a long standing interest in the evolution of eukaryotes and I think it's fair to say that Giardiasis is not the main focus of his research at the Marine Biological Laboratory in Woods Hole, Maine Massachusetts (USA) .

The Giardia lamblia genome is ~11.7 Mb in size (11,700,00 base pairs). This makes it about the same size as the yeast genome and the largest bacterial genomes. Mammalian genomes are about 200-300 times larger.

Preliminary results indicate 6470 genes distributed on five chromosomes. Most of the genes do not have introns and the average distance between genes is a few hundred nucleotides. What this means is that the genome is very compact with hardly any junk DNA (77% of the genome corresponds to coding regions as opposed to less than 2% in humans).

The introduction to the Morrison et al. (2007) paper has a nice summary of the main problems with relating Giardia to other eukaryotes.

Unusual features of this enigmatic protist include the presence of two similar, transcriptionally active diploid nuclei and the absence of mitochondria and peroxisomes. Giardia is a member of the Diplomonadida, which includes both free-living (e.g., Trepomonas) and parasitic species. The phylogenetic position of diplomonads and related excavate taxa is perplexing. Ribosomal RNA (rRNA), vacuolar ATPase (adenosine triphosphatase), and elongation factor phylogenies identify Giardia as a basal eukaryote (2–4). Other gene trees position diplomonads as one of many eukaryotic lineages that diverged nearly simultaneously with the opisthokonts and plants. Discoveries of a mitochondrial-like cpn60 gene and a mitosome imply that the absence of respiring mitochondria in Giardia may reflect adaptation to a microaerophilic life-style rather than divergence before the endosymbiosis of the mitochondrial ancestor.

Originally, it was thought that Giardia must be part of a group that diverged very early on in eukaryotic evolution, before other lineages acquired mitochondria. However, in the past ten years or so these amitochondrial species have been shown to contain genes that are clearly derived from mitiochondria (e.g., cpn60, dnaK). Thus, it now appears that these species have lost their original mitochondria, calling into question their position at the root of the eukaryotic tree.

One of the main surprises is the confirmation of what had long been suspected: Giardia is missing some common eukaryotic genes. The title of the paper highlights this finding: "Genomic Minimalism in the Early Diverging Intestinal Parasite Giardia lamblia."

In many cases the protein machines in Giardia are simpler than those in other eukaryotes and some key metabolic enzymes are not present. Is this a derived phenomenon resulting from a parasitic lifestyle or is it indicative of a primitive state in eukaryotic evolution?

Morrison et al. (2007) indicate their preference ...

As discussed earlier, Giardia consistently shows a pattern of simplified molecular machinery, cytoskeletal structure, and metabolic pathways compared to later diverging lineages such as fungi and even Trichomonas or Entamoeba (Supporting Online Material; table S7 and fig. S5). A parsimonious explanation of this pattern is that Giardia never had many components of what may be considered "eukaryotic machinery," not that it had and lost them through genome reduction as is evident for Encephalitozoon. Taking a whole-evidence approach, one sees that these data reflect early divergence, not a derived genome.

They attempt to construct phylogenetic trees based on a number of newly sequenced genes but immediately encountered problems.

Phylogenetic inference alone cannot resolve Giardia's evolutionary history. Because so many of Giardia's genes may have been derived from horizontal transfer or be subject to accelerated evolution, only a subset can be used to infer phylogeny. Of the ~1500 genes for which there are known homologs, only a handful included diverse eukaryotic taxa and generated robust trees, largely because the sequences could not be unambiguously aligned. We generated and examined trees for many conserved proteins, and selected ribosomal proteins for a multigene data set because they are an ancient family, whose nature—interaction with rRNAs and with all cellular proteins during their synthesis—constrains their divergence.

Their data suggests that Giardia and its close relatives form a lineage that branches deeply in the eukaryotic tree suggesting that they diverged very early on in eukaryotic evolution (above, from the supplemental data). (Probably close to two billion years ago.)

In an article accompanying the original paper, Keeling (2007) discusses the implications. He includes the phylogenetic tree shown here [Deep Questions in the Tree of Life].

Eukaryotic evolution. The hypothetical evolutionary tree consists of five "supergroups" based on several kinds of evidence (15). The branching order of supergroups is unresolved, implying that the relationships are unknown rather than a simultaneous radiation. CM indicates the presence of cryptic mitochondria (hydrogenosomes or mitosomes). A question mark indicates that no organelle has yet been found.

This is not a consensus tree by any stretch. The existence of the five groups is hotly contested and it remains to be seen whether these groupings will gain widespread support. Notice that Keeling does not commit to a branching order for the five groups in spite of the conclusions of Morrison et al. (2007) in the paper he is reviewing.

What is clear is that the old trees based on ribosomal RNA genes are not reliable and other genes will have to be examined in future work. That's the real significance of the Giardia lamblia genome sequence and the sequences of the genomes of other simple eukaryotes. Given that Giardia is missing some important genes—posibly because of its parasitic lifestyle—this may not be an easy task. Keeling (2007) sums it up like this ....

The outcome of this debate affects not only our understanding of early eukaryotic evolution, but also our view of Giardia biology. Simple characteristics could be primitive or derived via reduction, alternatives with very different meanings. The simplicity of Giardia's molecular systems differs from that of known derived parasites (1, 13). However, different lineages can follow different reductive paths (14), so determining Giardia's origins independently of its simplicity is essential. Given the depth of these questions, the new life that Morrison et al. have breathed into the debates is welcome, and will ensure continued attention on both a fascinating cell and the origin of eukaryotes.

[Photo Credits: The life cycle diagram is from the National Institutes of Health (USA) (Wikimedia Commons). The scanning electron micrograph of Giardia is from the Centers for Disease Control and Prevention (USA) (Wikimedia Commons)]

Seed magazine writers and influential science bloggers gather to discuss new directions in science communication. This lively panel discussion will cover a range of topics, including science and culture, public engagement with science, the role of scientists in the public discussion of science, and communication via the Internet, film, museums and other media. Author and journalist Chris Mooney, American University communications professor Matthew Nisbet, and University of Minnesota anthropologist Greg Laden will join moderator Jessica Marshall, a U of M science journalism professor. A reception in Dinkytown will follow the event. Co-sponsored by the Bell Museum of Natural History; Seed Magazine/ScienceBlogs; The Humphrey Institute's Center for Science, Technology and Public Policy; and the Minnesota Journalism Center.

WASHINGTON (CNN) -- A terrorist wanting to smuggle radioactive material from Canada into the United States probably would find it easy to do, a new report from congressional investigators said.

Government investigators were able to cross from Canada into the United States carrying a duffle bag with contents that looked like radioactive material and never encountered a law enforcement official, according to a report released Thursday by investigators from the Government Accountability Office.

"Our work clearly shows substantial vulnerabilities in the northern border to terrorist or criminals entering the United States undetected," the GAO's Greg Kutz testified Thursday at a Senate Finance Committee hearing on the topic.

"Although the southern border appears to be substantially more secure, we did identify several vulnerabilities on federally managed lands where there was no CBP [Customs and Border Protection] control."

It's our Southern border we Canadians should be worried about. There are far more terrorists in American than in Canada. Wake up Canadians! Don't you realize that terrorists from the USA could be infiltrating our country as we speak!? They're out to attack us because we're free ... well maybe not "free" but at least we're cheap now that the Canadian dollar has reached parity.

[Photo Credit: A border marker shows you where Canada ("left", or maybe right) meets the USA (right, I think) near Blumenort, Manitoba]

WASHINGTON (CNN) -- U.S. Secretary of State Condoleezza Rice on Thursday told delegates to a global climate change conference that countries around the world must work together to combat climate change, much as they cooperate against terror and the spread of disease.

"No one nation, no matter how much power or political will it possesses, can succeed alone," she said. "We all need partners, and we all need to work in concert."

Rice said the United States takes climate change seriously, "for we are both a major economy and a major emitter."

Other nations have been critical of the Bush administration's policy on climate change after the United States withdrew from the 1997 U.N. Framework Convention on Climate Change, known as the Kyoto Protocol. More than 150 countries signed the Kyoto agreement, which mandates limits on emissions.

Fight climate change like we fight terrorism. Work together, but drop out of Kyoto. No further comment is necessary. It saddens me that my Prime Minister is falling for this nonsense.

I was curious about when people were reading Sandwalk. Sometimes I get into chat mode with some of you in the comments section. It seems that some people have a schedule similar to mine.

Then I got to thinking. Maybe everyone in Europe reads during the night and everyone in Australia during the day—or some such permutation. So I took a snapshot of where my readers are at different times of the day/night.

Here are the results for 1PM, 5PM, 11PM, and 6AM respectively. There doesn't seem to be a pattern except that most of you are asleep between midnight and 6AM your time. It looks like you're surfing the internet most of the time you're awake! (BTW, who's that person in Hawaii? I'd like to visit you. Do you have a spare room?)

Polycystic liver disease (PLD) is associated with the formation of multiple cysts of various sizes in the liver. Sometimes it causes enlargement of the liver and abdominal pain but in most cases there are no symptoms and the patient may be unaware of any problem.

This disease is not the same as the often fatal polycystic kidney disease (PKD) [OMIM 173910] although patients suffering from kidney failure due to PKD will often have cysts in their liver as well.

PLD is inherited as an autosomal dominant trait, which means that you will have liver cysts even if you only inherit one mutant allele from one parent. There are probably several different genes that can be affected but two genes have been identified and characterized [OMIM 174050]. One of them is the SEC63 gene on chromosome 6q21 [OMIM 60648][Entrez Gene 11231]. This gene encodes one of the components of the ER membrane translocon. This is the pore through which newly synthesized is threaded following attachment of the ribosome/signal-recognition-particle complex [Signal Hypothesis] [Human Genes Involved in the Signal Hypothesis Pathway]. The defect in SEC63 probably interferes with sorting and secretion of proteins in the liver and this is what causes the cysts.

The Online Medelian Inheritance in Man (OMIM) database at Johns Hopkins University is one of the best databases in the world.The known alleles are null mutations meaning that they disrupt synthesis of the protein. It appears that the presence of one defective copy of the SEC63 gene has no effect on normal development or secretion in most tissues but does have a non-lethal effect in liver cells.

The other gene that's associated with polycystic liver disease is PRKCSH, a gene that encodes the β subunit of glucosidase II [OMIM 177060]. This protein plays a role in the glycolsylation of proteins in the endoplasmic reticulum [glycosylation]. Since glysosylation is requried for protein sorting and secretion, it is likely that interference in that process is resposible for liver cycsts. This is the same process that's defective in SEC63 mutants.

The Signal Hypothesis describes the mechanism whereby proteins that are destined to cross a membrane are synthesized. One of the key components of this pathway is Signal Recognition Particle or SRP. The structure of SRP is shown below from a paper by Maity and Weeks (2007)

Most of SRP is composed of an RNA molecule called 7SL RNA. It is shown as red and yellow helices in the bottom figure. The secondary structure is depicted in the top right-hand corner of the figure. There are six different proteins in SRP. All of them are bound to the RNA in one way or another. The six proteins are SRP9, SRP14, SRP54, SRP68, and SRP72. The numbers refer to the molecular mass in kilodaltons.

There are three genes for 7SL RNA. They are all found on chromosome 14 (above). Two of them are closely linked and the third one is somewhat farther away.

The three membrane components are the SRP receptor, the translocon (formerly known as ribophorin), and the signal peptidase. There are two subunits in the SRP receptor, α (docking protein) and β. The human genome contains a single gene for SRP receptor α subunit called SSPR (SSPRα). The genome has two separate genes for the β subunit called SSRB and SSR2.

There are 20 genes required for effective translocation of proteins with a signal sequence (only the SRP are shown on the chromosome maps). Additional proteins are required to assist in the translocation (chaperones) and in glycosylation of the protein once it enters the lumen of the endoplasmic reticulum.

The Senate approved a resolution today urging the Bush administration to designate Iran’s Islamic Revolutionary Guard Corps as a foreign terrorist organization, and lawmakers briefly set aside partisan differences to approve a measure calling for stepped-up diplomacy to forge a political solution in Iraq.

Since last month, the White House has been weighing whether to deem the entire Revolutionary Guard as a terrorist group or to take a narrower step focused only on the Quds Force, an elite unit of the corps. Either approach would signal a more confrontational posture by declaring a segment of the Iranian military to be a terrorist organization.

Saying that it's "confrontational" is putting it mildly. Is there a logical reason for doing this? Here's what General Petraeus says,

It quoted General Petraeus as saying it is “increasingly apparent to both coalition and Iraqi leaders that Iran, through the use of the Iranian Republican Guard Corps Quds Force, seeks to turn the Shiite militia extremists into a Hezbollah-like force to serve its interests and fight a proxy war against the Iraqi state and coalition forces in Iraq.”

Ahhh .... now I get it. We have a case where foreign soldiers in Iraq might be helping certain militia groups in order to serve its own interests and fight a proxy war against its perceived enemies. All soldiers who do that are terrorists, right?

Makes a lot of sense to me.

As an aside, I note that the US Congress is a lot more confident about military intelligence these days. I guess the fiasco of Colin Powell's UN Presentation on February 6, 2003 has been forgotten in light of a vastly improved intelligence gathering network. We can now be confident that all pronouncements about the evil axis countries are accurate, right?

Under the list of "Skills that biochemistry and molecular biology students should obtain by the time they have finished their undergraduate program," there are a number of motherhood type statements. One of them is "Ability to assess primary papers critically." We've been discussing these required skills for the past few months. I've questioned the wisdom of teaching undergraduates how to critically evaluate the scientific literature because I think it's a skill that only comes after a lot of experience in the discipline.

There are many confusing papers out there and it's difficult to decide what's right and what's wrong. We can give students our opinion but that's not the same as teaching them how to critically evaluate a paper.

Here's an example of how difficult it is to read the scientific literature. A recent paper by John Stiller (2007) promotes the idea that plants are more closely related to animals than fungi. Here's the abstract.

Evolutionary relationships among complex, multicellular eukaryotes are generally interpreted within the framework of molecular sequence-based phylogenies that suggest green plants and animals are only distantly related on the eukaryotic tree. However, important anomalies have been reported in phylogenomic analyses, including several that relate specifically to green plant evolution. In addition, plants and animals share molecular, biochemical and genome-level features that suggest a relatively close relationship between the two groups. This article explores the impacts of plastid endosymbioses on nuclear genomes, how they can explain incongruent phylogenetic signals in molecular data sets and reconcile conflicts among different sources of comparative data. Specifically, I argue that the large influx of plastid DNA into plant and algal nuclear genomes has resulted in tree-building artifacts that obscure a relatively close evolutionary relationship between green plants and animals.

How do you explain this to undergraduates? How can you teach them to critically evaluate such a paper when, on the surface, it seems perfectly reasonable and the data seems sound? I submit that most of us work within a model of how we think the history of life has developed over millions of years. That model is based on reading hundreds of papers and getting a "feel" for the data. Some papers are rejected and some are given more credence and this is based on all kinds of intangibles—including the reputation of the authors. Can undergraduates be taught such a thing? I don't think so.

The Presentation speech was delivered on Dec. 10, 1999 by Professor Ralf Pettersson of the Nobel Committee at Karolinska Institutet. The drawing depicts the first version of the Signal Hypothesis in 1971 from the Nobel Lecture.

Your Majesties, Your Royal Highness, Ladies and Gentlemen,

Imagine a large factory that manufactures thousands of different items in millions of copies every hour, that promptly packages and ships each of them to waiting customers. Naturally, to avoid chaos, each product requires a clearly labeled address tag. Günter Blobel is being awarded this year's Nobel Prize in Physiology or Medicine for having shown that newly synthesized proteins, analogous to the products manufactured in the factory, contain built-in signals, or address tags, that direct them to their proper cellular destination.

An adult human is comprised of approximately 100,000 billion cells, all of which are structurally similar. A striking feature is that each cell contains small compartments or organelles. Organelles are bounded by impermeant, lipid-rich membranes that ensure the physical and functional separation of vital biochemical processes. This compartmentalization enables cells to be compared to a large city in which each public function is housed in a separate building. The blueprint for all cellular processes is maintained in the genome located in the cell nucleus, the City Hall of the cell. Energy production takes place within mitochondria, the power plant of the cell; the breakdown and recycling of waste takes place in the lysosome etc. The production of new products, proteins in the case of the cell, is carried out by ribosomes in a process resembling an assembly line. There is indeed a feverish amount of activity within cells. Every second, thousands of protein molecules are degraded and replaced by new ones. How does a newly made protein get to its correct intracellular location, and how do proteins enter into and move across the membranes surrounding individual organelles? These two central questions occupied the minds of scientists during the 1960s.

Günter Blobel has provided the answer to both these questions. In 1967 he joined the renowned cell biology laboratory headed by George Palade at the Rockefeller University in New York. Palade, who received the Nobel Prize in 1974, had defined and charted the route that secretory proteins take from their site of synthesis within the cell to the cell surface. Secreted proteins are made in the cell in association with a membrane system called the endoplasmic reticulum.

Blobel began by examining how a newly synthesized secretory protein is targeted to and then translocated across the endoplasmic reticulum membrane. Based on the results from a series of elegant experiments, Blobel put forth the so-called "signal hypothesis," in a preliminary form in 1971 and a mature final form in 1975, to explain how this process takes place. The signal hypothesis postulated that newly made proteins contain built-in signals, address tags or zip codes, that target proteins to the endoplasmic reticulum and that subsequently lead them across the reticulum membrane through a specialized channel. Proteins that are translocated across to the other side are packaged for subsequent transport to the cell surface.

To test this hypothesis, Blobel developed an ingenious experimental test tube system, which enabled him to individually study each step of the process. The system which relied on components obtained from mouse, rabbit, and dog cells, laid the foundation for the development of the field of molecular cell biological research. In the following 20 years, Blobel and his co-workers characterized this complex process in great detail. The original signal hypothesis, in all its essential parts, has stood the test of time and proven to be correct.

Blobel extended his studies and was able to demonstrate that proteins destined to become transported to other organelles, or that become integrated into different cellular membranes, also contain specific address tags and so-called "topogenic" signals. The guiding principles that Blobel has helped to elucidate are universally applicable and highly conserved. They have remained almost unchanged during the course of evolution, functioning in yeast, plant, and animal cells.

Perhaps the most important consequences of Günter Blobel's discoveries is that we now understand the fundamental principles guiding the formation and maintenance of cell and organelle structure. The signal hypothesis provides a framework to understand the mechanisms underlying many hereditary diseases and other disease processes in which specific proteins become mislocalized. In addition, these discoveries have enabled the pharmaceutical industry to turn cultured cells into efficient mini-factories for the production of protein-based drugs, such as insulin, growth hormone, coagulation factors, etc.

Günter Blobel, your discovery that proteins contain built-in signals that direct them to their correct destination within cells and across membranes has had a profound impact on our understanding of how a cell and its organelles are assembled and maintained. Your work has also laid the foundation for modern molecular cell biology. On behalf of the Nobel Assembly at Karolinska Institutet I wish to convey to you my warmest congratulations and I now ask you to step forward to receive your Nobel Prize from the hands of His Majesty the King.

One interesting thing that leapt out at me when reading this was the fact that, while many scientists now realize that it was a mistake to jump to the conclusion that there were massive amounts of "junk" in DNA (because they were trying to fit the research into a Darwinian model), they are on the verge of committing the same exact mistake all over again, this time with RNA.

In order to understand such a bizarre question you have to put yourself in the shoes of an IDiot. They firmly believe that the concept of junk DNA has been overturned by recent scientific results. According to them, the predictions of Intelligent Design Creationism have been vindicated and all of the junk DNA has a function.

Now the IDiots have turned their attention to RNA. They fell hook line and sinker for the hype about functional sequences in junk DNA and they're falling just as easily for the hype about new RNAs. They believe all those silly papers that attribute function to every concevable RNA molecule that has ever been predicted or detected in some assay.

The IDiots were wrong about junk DNA and they're wrong about RNA. The answer to my question is "yes," the IDiots will make the same mistake. You can practically count on it. The answer to Crowther's question is "no." Most (but not all) scientists did not fall for the spin on junk DNA and they realize that the vast majority of our genome is junk. In the long run, they will not fall for the claim that most of the junk DNA is functional because it encodes essential RNA molecules.

According to Transparency International Canada is in 9th place in terms of corruption. I think our dismal showing is because university Professors don't ask for bribes like they do in other countries. We should change that. From now on an "A" is going for $1000 and if you want a "B" it will only cost you $600!

The signal recognition particle binds to ribosomes at the site of the exit tunnel and interacts with the N-terminal end of newly synthesized protein. If the protein contains a signal sequence then protein synthesis is temporarily arrested. The complex is directed to the membrane surface and the end of the protein is inserted through a pore in the membrane. Protein synthesis then continues and the newly synthesized protein is inserted into the endoplasmic reticulum in eukaryotes or across the plasma membrane in bacteria [The Signal Hypothesis].In all species (bacteria and eukaryotes) the signal recognition particle is composed of a conserved ~300 nucleotide RNA molecule (7SL/7S RNA) and several (usually six) proteins. Only one of the proteins is common to both bacteria and eukaryotes (Hainzl et al. 2007). The organization of the mammalian SRP is shown above (Maity and Weeks, 2007).

There are two distinct regions of SRP. The large subunit consists of nucleotides 101-255 of the 7S RNA molecule. The RNA is folded into the secondary structure shown on the left (Mauty and Weeks, 2007). In this diagram, the linear nucleotide sequence is connected by solid lines with arrows and the dashed lines depict hydrogen bond interactions between bases that are brought into proximity by the secondary, and tertiary, structure of the RNA molecule.

Four proteins (SRP19, SRP54, SRP68, SRP72) are bound to the large subunit. SRP54 is the only protein found in all species. The large subunit recognizes the signal peptide and binds to the membrane receptor.

The other subunit is called the Alu subunit. The significance of this name will become clear in another posting. The RNA component consists of nucleotides 1-100 and 256-299 arranged in a single double helical structure. Proteins SRP9 and SRP14 bind to the Alu subunit. The Alu subunit is responsible for arresting protein synthesis.

SRP is an important cellular component and it plays a crucial role in protein synthesis and protein trafficing. It's also a good example of a ribonucleotide particle present in all species. Most people don't appreciate the fact that many small RNAs are an integral part of the cellular machinery. Other examples are the telomerase complex and RNAse P. These small RNAs have been known for a long time. The recent publicity about other types of small RNAs has unfortunately conveyed the impression that this is a new discovery.

The structure of SRP has not been fully worked out but a great deal is known about the various components. A model of the complete mammalian signal recognition particle, incorporating the known structures of the RNA and the various proteins, is shown below (Halic and Beckmann, 2005).

Heparin (left) is an oligosaccharide bound to a very specific protein to form heparin proteoglycan. The physiologically important oligosaccharide is called heparan sulfate. It is found on the surface of normal endothelial cells and it is this molecule that binds antithrombin III. The interaction of heparan sulfate and antithrombin III inhibits blood clotting [Inhibiting Blood Clots: Anticoagulants].

It is very difficult to synthesize heparan sulfate so the synthetic drug is quite expensive. The results of a number of studies indicated that the exact structure of each of the sugar residues (rings) was very important for proper anticoagulant activity as was the position of the sulfate groups (those with "S" that are bound to the rings).

Theme

Blood ClottingA recent paper by Chen et al. (2007) shows that simpler forms of the heparin-like oligosaccharide have significant anticoagulation activity. They started with a compound called N-sulfo heparosan, which is prepared from bacterial oligosaccharides by a combination of enzymatic and chemical steps. This starting material was then modified using various recombinant enzymes to produce a large class of heparin-like molecules. One of these derivatives, recomparin (below left) (Lindhardt and Kim, 2007) had significant anticoagulation activity. (Click on the figure to enlarge.)

The result is significant because recomparin does not have the modified rearranged sugar (iduronic acid, IdoUA)that was previously thought to be essential for anticoagulation activity. The modification of the oligosacchraide to create the iduronic acid residues was complicated an inefficient. Thus, the new recomparin drug will be much cheaper to make.

April 5, 2007Blood Clotting: Intrinsic Activity. The role of factors VIII and IX. Deficiencies in Factor VIII cause hemophilia A an X-linked form of hemophilia that was common in European royal families descending from Queen Victoria.

Laurence A. Moran

Larry Moran is a Professor Emeritus in the Department of Biochemistry at the University of Toronto. You can contact him by looking up his email address on the University of Toronto website.

Sandwalk

The Sandwalk is the path behind the home of Charles Darwin where he used to walk every day, thinking about science. You can see the path in the woods in the upper left-hand corner of this image.

Disclaimer

Some readers of this blog may be under the impression that my personal opinions represent the official position of Canada, the Province of Ontario, the City of Toronto, the University of Toronto, the Faculty of Medicine, or the Department of Biochemistry. All of these institutions, plus every single one of my colleagues, students, friends, and relatives, want you to know that I do not speak for them. You should also know that they don't speak for me.

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Quotations

The old argument of design in nature, as given by Paley, which formerly seemed to me to be so conclusive, fails, now that the law of natural selection has been discovered. We can no longer argue that, for instance, the beautiful hinge of a bivalve shell must have been made by an intelligent being, like the hinge of a door by man. There seems to be no more design in the variability of organic beings and in the action of natural selection, than in the course which the wind blows.Charles Darwin (c1880)Although I am fully convinced of the truth of the views given in this volume, I by no means expect to convince experienced naturalists whose minds are stocked with a multitude of facts all viewed, during a long course of years, from a point of view directly opposite to mine. It is so easy to hide our ignorance under such expressions as "plan of creation," "unity of design," etc., and to think that we give an explanation when we only restate a fact. Any one whose disposition leads him to attach more weight to unexplained difficulties than to the explanation of a certain number of facts will certainly reject the theory.

Charles Darwin (1859)Science reveals where religion conceals. Where religion purports to explain, it actually resorts to tautology. To assert that "God did it" is no more than an admission of ignorance dressed deceitfully as an explanation...

Quotations

The world is not inhabited exclusively by fools, and when a subject arouses intense interest, as this one has, something other than semantics is usually at stake.
Stephen Jay Gould (1982)
I have championed contingency, and will continue to do so, because its large realm and legitimate claims have been so poorly attended by evolutionary scientists who cannot discern the beat of this different drummer while their brains and ears remain tuned to only the sounds of general theory.
Stephen Jay Gould (2002) p.1339
The essence of Darwinism lies in its claim that natural selection creates the fit. Variation is ubiquitous and random in direction. It supplies raw material only. Natural selection directs the course of evolutionary change.
Stephen Jay Gould (1977)
Rudyard Kipling asked how the leopard got its spots, the rhino its wrinkled skin. He called his answers "just-so stories." When evolutionists try to explain form and behavior, they also tell just-so stories—and the agent is natural selection. Virtuosity in invention replaces testability as the criterion for acceptance.
Stephen Jay Gould (1980)
Since 'change of gene frequencies in populations' is the 'official' definition of evolution, randomness has transgressed Darwin's border and asserted itself as an agent of evolutionary change.
Stephen Jay Gould (1983) p.335
The first commandment for all versions of NOMA might be summarized by stating: "Thou shalt not mix the magisteria by claiming that God directly ordains important events in the history of nature by special interference knowable only through revelation and not accessible to science." In common parlance, we refer to such special interference as "miracle"—operationally defined as a unique and temporary suspension of natural law to reorder the facts of nature by divine fiat.
Stephen Jay Gould (1999) p.84

Quotations

My own view is that conclusions about the evolution of human behavior should be based on research at least as rigorous as that used in studying nonhuman animals. And if you read the animal behavior journals, you'll see that this requirement sets the bar pretty high, so that many assertions about evolutionary psychology sink without a trace.

Jerry Coyne
Why Evolution Is TrueI once made the remark that two things disappeared in 1990: one was communism, the other was biochemistry and that only one of them should be allowed to come back.

Sydney Brenner
TIBS Dec. 2000
It is naïve to think that if a species' environment changes the species must adapt or else become extinct.... Just as a changed environment need not set in motion selection for new adaptations, new adaptations may evolve in an unchanging environment if new mutations arise that are superior to any pre-existing variations

Douglas Futuyma
One of the most frightening things in the Western world, and in this country in particular, is the number of people who believe in things that are scientifically false. If someone tells me that the earth is less than 10,000 years old, in my opinion he should see a psychiatrist.

Francis Crick
There will be no difficulty in computers being adapted to biology. There will be luddites. But they will be buried.

Sydney Brenner
An atheist before Darwin could have said, following Hume: 'I have no explanation for complex biological design. All I know is that God isn't a good explanation, so we must wait and hope that somebody comes up with a better one.' I can't help feeling that such a position, though logically sound, would have left one feeling pretty unsatisfied, and that although atheism might have been logically tenable before Darwin, Darwin made it possible to be an intellectually fulfilled atheist

Richard Dawkins
Another curious aspect of the theory of evolution is that everybody thinks he understand it. I mean philosophers, social scientists, and so on. While in fact very few people understand it, actually as it stands, even as it stood when Darwin expressed it, and even less as we now may be able to understand it in biology.

Jacques Monod
The false view of evolution as a process of global optimizing has been applied literally by engineers who, taken in by a mistaken metaphor, have attempted to find globally optimal solutions to design problems by writing programs that model evolution by natural selection.